The CoQH2/CoQ Ratio Serves as a Sensor of Respiratory Chain Efficiency

• High CoQH2/CoQ ratio induces reverse electron transport under physiological conditions
• RET-generated ROS induces partial complex I degradation
• Increase in the CIII fraction detached of CI optimizes mETC to consume fatty acids
• The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency

SummaryElectrons feed into the mitochondrial electron transport chain (mETC) from NAD- or FAD-dependent enzymes. A shift from glucose to fatty acids increases electron flux through FAD, which can saturate the oxidation capacity of the dedicated coenzyme Q (CoQ) pool and result in the generation of reactive oxygen species. To prevent this, the mETC superstructure can be reconfigured through the degradation of respiratory complex I, liberating associated complex III to increase electron flux via FAD at the expense of NAD. Here, we demonstrate that this adaptation is driven by the ratio of reduced to oxidized CoQ. Saturation of CoQ oxidation capacity induces reverse electron transport from reduced CoQ to complex I, and the resulting local generation of superoxide oxidizes specific complex I proteins, triggering their degradation and the disintegration of the complex. Thus, CoQ redox status acts as a metabolic sensor that fine-tunes mETC configuration in order to match the prevailing substrate profile.

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